The urinary physiological pH is typically of the order of about 5 to 5.5.
The related diseases are generally metabolic diseases that can induce urinary lithiases as secondary symptoms. The most classical example is type 2 diabetes or fat diabetes which induces acidosis and hyperuricuria and in consequence induces urinary calculi of uric acid, which can be prevented by alkalization of the urine.
The related diseases can also be kidney diseases, as will be explained below.
Urinary lithiasis is a disease consisting of the formation of calculi in the urinary tract. A urinary calculus consists mainly of crystalline substances. Crystallization is highly dependent to saturation of the urine with crystallizable compounds such as calcium, oxalate, phosphorus, magnesium, bicarbonate, uric acid, urate, sodium or cystine. These various compounds eliminated in the urine are therefore directly involved, through their concentration and their tendency to crystallize, in the formation of calculi. However, this tendency is also influenced by various crystallization inhibiting or inducing substances. Thus, citrate and by extension the Krebs cycle precursor salts, which will increase citraturia as a secondary effect, have an inhibitory action on the formation of calculi by limiting or even preventing crystal growth, aggregation and nucleation in vitro and in vivo.
Urinary acidosis and/or hypocitraturia and/or hypercalciuria and/or hyperoxaluria are factors promoting urinary lithiasis. One treatment for certain urinary lithiases is alkalization of the urine. In fact, the solubility of certain substances, such as cystine and uric acid, is reduced in an acidic environment. Alkaline compositions comprising alkaline salts are generally indicated in the treatment of urinary acidosis. Moreover, many disorders and therapeutic situations involving the kidney or other organs can induce metabolic acidosis. For example, chronic and acute renal failure, the sequelae of renal grafts, or renal tubular acidoses, certain renal tubulopathies including cystinuria, as well as certain hereditary or non-hereditary metabolic diseases, for example hereditary distal tubular acidoses (cystinoses), diabetes and certain intoxications may be mentioned.
Alkalization should allow the urinary pH to be maintained permanently in a given range (6.5 to 7.0 in the case of oxalocalcium or uric acid crystals, 7.0 to 8.0 in the case of cystine crystals). Without treatment, the physiological pH of the urine is generally in a range from 5.0 to 5.5, or even from 5.0 to 6.0. This pH can reach a minimum value of the order of 4.4. It is all the more difficult to maintain the urinary pH at a high value when the physiological pH of the urine is low.
Among the alkaline salts used, the bicarbonate salts, and more particularly sodium bicarbonate, which is for example present in Vichy water, and potassium bicarbonate may be mentioned. Compositions comprising these salts are most often magistral preparations, with immediate effect. However, it should be emphasized that the bicarbonate salts have an unpleasant taste, making regular daily administration difficult.
A certain number of kidney diseases lead to loss of bicarbonate, such as distal tubular acidoses, kidney diseases with renal loss of bicarbonate (especially following kidney transplants or renal hypoplasia), renal failure with acidoses and Fanconi syndrome. Bicarbonate salts are commonly administered for correcting this loss of bicarbonate.
One of the advantages of the bicarbonate salts is that their absorption into the organism via the intestinal tract is independent of the pH. Another advantage of the bicarbonate salts is that they allow reinforcement of the quantity of citrate present in the urine. In fact, bicarbonate is a product of degradation of citrate in the organism. In the case of severe alkalosis (due to a high loading of bicarbonate), excretion of citrate is increased by two mechanisms: increase in endogenous synthesis of citrate and increase in secretion of citrate in the urine. Thus, bicarbonate can also be used for combating hypocitraturia.
Administration of sodium bicarbonate or potassium bicarbonate at high doses (30 to 40 grams per day) most often makes it possible to maintain urinary pH permanently above 7.6, but causes manifestations of metabolic alkalosis or digestive disorders, mainly diarrhoea.
Therefore a drawback of ingesting bicarbonate salt is its low gastric tolerance at high doses.
Administration of sodium bicarbonate or potassium bicarbonate at lower doses, from 8 to 16 grams per day in 2 to 3 liters of water well distributed over a 24-hour period, can provide alkalization of the urine. However, such a distribution over a 24-hour period requires an administration every two hours, which is very restricting for the patient. The treatment is therefore very often followed imperfectly.
Document EP 1 970 066 and especially the work by Breitkreutz et al., “Enteric-coated solid dosage forms containing sodium bicarbonate as a drug substance: an exception from the rule?”, JPP 2007, 59: 59-65 (2007), as well as the notice given in the Compendium Suisse des Médicaments [Swiss Compendium of Medicaments], describe a medicament, Nephrotrans, in the form of soft capsules comprising sodium bicarbonate at a unit dose of 500 mg per capsule, prescribed for the treatment of metabolic hyperacidity of the blood (metabolic acidosis) and for maintenance treatment for preventing recurrence of excessive metabolic acidosis in chronic renal failure. The therapeutic use of this medicament is very different from the therapeutic use envisaged according to the present invention, namely alkalization of the urine and/or treatment and/or prevention of urinary lithiases and related diseases, occurring at a physiological pH and/or during urinary acidosis and/or during hypobicarbonataemia and/or during hypocitraturia and/or during hypercalciuria and/or during hyperoxaluria. Moreover, the medicament Nephrotrans has the particular property of being very resistant to the gastric juice. In fact, the work by Breitkreutz et al. demonstrates that, whether at pH 1 or at pH 4.5, the Nephrotrans capsule does not produce any (or hardly any) release of sodium bicarbonate for several hours. Moreover, this publication shows that Nephrotrans releases the sodium bicarbonate in 5 to 6 hours, as after 5 hours only 14-16% of the sodium bicarbonate remains in the capsule.
Moreover, the bicarbonate salt is present in a proportion (also called “loading”) of about 37.5% by weight, relative to the total composition of Nephrotrans.
The bicarbonate salt according to Nephrotrans is therefore released according to the pH of the dissolution medium. In vivo, its release is therefore delayed when the product goes into the small intestine, and is limited in time. Such release certainly does not allow an alkaline urinary pH to be maintained continuously for up to 8 to 12 h.
In any case, alkalization of the urine is not optimum with the existing pharmaceutical compositions, even with proper compliance with the basic treatment. In particular, a large reduction in urinary pH is recorded during the night, the period that is most favourable to lithogenesis.
Moreover, maintaining an alkaline urinary pH over the long term presents a risk of precipitation of calcium phosphate, making the urinary calculus mixed, especially in the case of associated hypercalciuria. Finally, patients treated with Vichy water, which contains 3.5 g/L of sodium bicarbonate, can have long-term exposure to fluorosis, especially if there is renal failure.
Thus, there is still a need for a pharmaceutical composition that would advantageously permit passage of the bicarbonate salt along the whole intestinal tract in a controlled, and sustained, manner over at least about 6 to 8 hours, even more preferably over more than about 8 hours. The pharmaceutical composition according to the invention therefore generally, and particularly advantageously, permits release of the bicarbonate salt essentially over a period of about 6 to 12 h, preferably of about 8 h to 12 h.
The composition according to the invention addresses these problems, as it makes it possible to retain the advantages of the bicarbonate salts, while avoiding the drawbacks mentioned above.